The present invention generally relates to metal surfaces of medical devices which are rendered biocompatible, to medical devices including same, to processes for preparing same, and to implanting procedures utilizing same. More specifically, the biocompatible metal surfaces include an amino-functional organosilane which is covalently linked to metal oxides on the metal surface of the device while covalently linking a biologically active agent thereto and thereby to a silane-treated metal surface. This surface has biocompatibility characteristics while simultaneously presenting a surface which encourages endothelialization upon implantation within a blood vessel and the like.
The importance of biocompatibility of surfaces of various medical devices is well-known and has been sought after for many years and through a variety of approaches. Enhanced biocompatibility is needed, of course, when medical devices are to be implanted within a living body for extended time periods including those which are considered to be of a permanent or semi-permanent nature. It is well-known that, generally speaking, biocompatibility properties are enhanced by attempting to secure biologically active agents to surfaces of medical devices, particularly those which contact flowing blood when they are implanted or otherwise used during medical procedures and the like. In many instances, it is particularly undesirable to have the biologically active agent leach away in wet environments such as are encountered by medical devices that engage blood or other body fluids. Many approaches in this area have concentrated on utilizing polymeric surfaces as the surface which encounters the body fluids and then treating those polymeric surfaces according to a variety of procedures. Other approaches have attempted to treat metallic surfaces which are intended to contact body fluids during implantation and the like. Polymeric surfaces and metallic surfaces each pose different problems which must be overcome in order to provide a polymeric or metallic surface that is suitable for implantation and/or extended-time residence within the body.
Generally speaking, the types of treatments which have been implemented or attempted fall into three broad categories. One involves plasma discharge treatments of the medical device surface. Another requires only dipping or similar means for contacting the surface with specific chemical components under treatment conditions (such as elevated temperature) which are less elaborate than plasma discharge treatments. A further treatment type involves chemically oxidizing the metallic surface, such as a tantalum, until enough of a metal oxide layer is provided for bonding.
The present invention avoids the need for plasma discharge treatments while at the same time providing effectively modified metallic surfaces. U.S. Pat. Nos. 3,549,409 and 3,639,141 describe treatments of particular polymeric surfaces by swelling the polymeric surface, bonding an agent thereto and non-covalently coupling heparin to that agent. The latter of these patents mentions contacting the polymeric surface with an amino alkyl trialkoxysilane dissolved in an organic solvent which swells the polymeric material. Another chemical treatment approach is exemplified by U.S. Pat. Nos. 4,526,714 and 4,634,762 which indicate that a surface can be rendered biocompatible by coating it with a conjugate of heparinous material and a protein, with the conjugate being formed by coupling carried out in the presence of 1-ethyl-3-dimethyl-aminopropyl carbodiimide (known as EDC) and the like as a coupling agent. The conjugate is attached to the substrate surface at the sites where the surface free functional groups suitable for binding to the conjugate are present. In order to effect the coupling needed to form this conjugate, these free functional groups on the substrate surface are provided as free amino groups.
Another type of treating procedure which has been suggested and attempted involves treatment of a surface with heparin benzalkonium chloride (known as HBAC). A quaternary amine structure is involved. The result is an ionic linkage, and ionic exchange occurs quite readily. For example, HBAC is easily leached from the treated surface to the extent that substantially all of the heparin is removed within about three days under leaching conditions. In addition, 4M guanidine quickly removes the heparin during a non-physiological test, typically within one hour. Furthermore, because benzalkonium chloride is in essence a surfactant, HBAC is a cytotoxic material as well as a hemolytic material which causes a breakdown of red blood cells.
Other quaternary amine alternatives are believed to be non-hemolytic, for example, tetradodecylammonium chloride (known as TDMAC). These types of materials, which are typically applied from a hydrocarbon solvent system, also provide ionic bonding, and ionic exchange can and does occur quite readily. Because of its molecular structure, heparin and materials having similar functions do not escape quite as readily from TDMAC as for HBAC, but leaching is still very apparent. When attachment to a surface is by means of ionic bonding of TDMAC and the like, most of the heparin or the like is leached away after three hours of contact with blood plasma or after about 24 hours when within a phosphate buffered saline solution under physiological conditions. The ionically attached material is substantially completely removed with guanidine within about one hour during non-physiological testing.
Many of the previous attempts do not fare well under in vivo or biological conditions, and they fall short of fulfilling desirable attributes such as having the coating remain functional for a length of time adequate to provide maximum thrombus prevention. Another particularly important consideration is whether or not the coating interferes with endothelialization. For metallic medical devices which undergo movement such as bending of a portion thereof during implantation and/or use, the mechanical properties of the treatment coating should be able to withstand flexure such as during expansion and the like of the coated member. Exemplary in this regard are metallic radially expandable generally tubularly shaped endoprostheses which are generally known as stents. An exemplary stent in this regard is described in U.S. Pat. No. 5,019,090, the subject matter thereof being incorporated by reference hereinto. Stents such as these are made of very fine gauge metallic wire, typically tantalum wire or stainless steel wire. During implantation, these stents are mounted onto the balloon of an angioplasty catheter or the like until a partially occluded location along a blood vessel or the like is reached, at which time the balloon and the stent are radially and circumferentially expanded for purposes of opening the occlusion and supporting the vessel at that location. This necessarily involves rather extensive bending of the tantalum wire. Many previously available coatings do not have the flexibility and/or adherence properties which are needed to avoid cracking and/or loss of the coating when subjected to this type of flexure.
It is accordingly desirable to be able to utilize a system which meets the objectives of imparting biocompatibility attributes to a metallic substrate so as to substantially prevent thrombus formation on this surface. Furthermore, the system should not crack or otherwise deteriorate due to mechanical movement of the treated metallic member, the system should not allow substantial leaching of the biologically active material, and the system should not substantially interfere with endothelialization after implantation has been completed.
It has been determined that a system providing covalent linkages between a biologically active agent and a metallic surface meets all of these objectives. This includes treatment of the metallic surface of a medical device with an organosilane having amine reactive sites. The organosilane is covalently linked by a condensation reaction with metal oxides of the metallic surface. A biologically active agent such as heparin is applied to the organosilane-coated metallic member, there being a covalent linkage between amine reactive sites of the organosilane and carboxyl moieties or the like of the biologically active agent. Implanting of this device within a blood vessel and the like substantially prevents thrombus formation on the metallic member without significantly interfering with endothelialization of the metallic member. Also, experimental evidence suggests heparin will help modulate smooth muscle cell proliferation associated with re-stenosis or re-occlusion of the dilated vessel.
It is accordingly a general object of the present invention to provide an improved biocompatible metal surface, a method of preparing same, and a method of implanting which utilizes same.
Another object of the present invention is to provide an improved stent or other medical device having a coating treatment which is of a covalent nature and is able to withstand flexure and interaction with fluids.
Another object of this invention is to provide an improved biocompatible metallic surface and method of making same with a covalent linkage between a mucopolysaccharide or a glucose amine and a metallic surface.
Another object of the present invention is to provide an improved implanting method whereby a covalently treated metallic member prevents thrombus formation thereon and does not significantly interfere with endothelialization thereof.
Another object of this invention is to provide an improved metallic stent which is particularly compatible and exhibits advantageous properties conducive of long-term placement within the body.
Another object of the present invention is to provide a stable functionalized metal surface for covalently binding bioactive agents thereto.
Another object of the present invention is to provide a treatment of even fine metal wires without detrimentally affecting the mechanical properties of the metal.
These and other objects, features and advantages of the present invention will be clearly understood through a consideration of the following detailed description.